US3254112A - Substituted tertiary amino compounds having valuable pharmacological properties - Google Patents

Description

May 31, 1966 KRALT ETAL 3254,112

SUBSTITUTED TERTIARY AMINO COMPOUNDS HAVING VALUABLE PHARMACOLOGICAL PROPERTIES Filed May 16, 1963 3 Sheets-Sheet 2 INVENTORS IK OED WILLEM J. ASMA ADOLF LINDN? United States Patent O sunsrrrrrrnn 'IERTAR AMINO CMPOUNDS HAVING VALUABLE PHARMACOLOGICAL rnornnrrns Tennis Kralt, Hendrik Dnrk Moed, and Willem Johannes This invention relates to substituted tertiary amino compounds having valuable pharrnacological properties.

This application is a continuation-in-part of the applicants copending application Serial Number 802,677, filed March 30, 1959 and now abandoned and the applicants copending application Serial Number 773,763, filed November 13, 1958 and now abandoned. Said application Serial Number 773,763 was a continuation-in-part of U.S. Serial No 727,394, filed April 9, 1958 now abandoned.

In said parent applications the compounds recited were al1 described as being active in the lowering of blood pressure and as having spasrnolytic activities. The compounds of the instant case are those compounds of the parent cases which are primarily useful as spasmolytic agents.

More particularly the compounds of the instant case are aralkylamino-esters of a nuclear substituted benzoic acid selected from the group consisting of the free base of the formula A wheren R and R are each selected from the group consisting of hydrogen and alkoxy of 1-4 carbon atoms, R is alkoxy of 1-4 carbon atoms, R; is selected from the group consisting of hydrogen and hydroxy, R is selected from the group consisting of hydrogen and alkyl of 1-4 carbon atoms, R is alkyl of 1-6 carbon atoms, R, and R are each selected from the group consisting of hydrogen, hydroxy and alkoxy of 1-4 carbon atoms with the proviso that at least one of R and R is selected from the group consisting of hydroxy and alkoxy and Y is alkylene of 1-8 carbon atoms, the free base of the formule. B

wheren R R and R are each selected from the group consisting of H, OH and alkoxy of 1-4 carbon atoms, R; is selected from the group consistng of H and OH, R is alkyl of 1-4 carbon atoms, R is selected from the group consisting of alkyl of 1-6 carbon atoms and benzyl, Y is selected from the group consisting of cyclohexene and alkylene of 1-8 carbon atoms, and R R and R are each selected from the group consisting of OH and alkoxy of 14 carbon atoms and their nontoxic acid addition salts.

Especially important in the compounds of -formula A is the combination: R is hydrogen and R is a hydroxy or an alkoxy group and the cases in Which R and R are both either an alkoxy group or a hydroxy group.

If the left-hand and/or the right-hand benzene core contains more than one alkoxy group, these compounds are preferred, in which these substituents are identcal groups.

Patenized May 31, 1966 In the compounds according to the forrnula A, if the groups R R R and R represent alkoxy groups, they contan preferably alower aliphatic carbon chain with 1 to 4 carbon atoms, particularly a mthyl or an ethyl group.

In the compounds of the formula A to be described hereinafter the alkoxy groups of the left-hand and the right-hand benzene core are preferably bound to the para carbon atom, to the paraand to one meta-carbon atom and to the paraand the two meta-carbon atoms.

If in the compounds of the formula A R is an alkyl group, this contains preferably 1 to 4 carbon atoms and it is particularly a methyl group, R is preferably an alkyl group having 1 to 6 carbon atoms, particularly an alkyl group with 2 or 3 carbon atoms, for example an ethyl-, propylor isopropyl group. If Y designates an alkylene group, t contains 1 to 8 carbon atoms, preferably 3 to 7 carbon atoms.

The compounds according to the invention may be producedin various ways. These methods are designated in the present application by AB, C, D and E.

In accordance with Method A a compound of the formula I (see formula sheet) reacts with one of the compounds of the formulae IIa, IIb and IIc. In these and in the further following formulae R to R and Y designate the groups or atoms as indicated above, unless it is stated otherwise. In formula Ilb R designates a lower aliphatic hydrocarbon radical, for example methyl or ethyl and Hlg indicates a chlorine or a bromine atom. hydrogen, hydroxy or alkoxy of 1 to 4 carbon atoms.

According to Method B a compound of the ormula XII is coupled with a compound of the formula XIII. In the last-mentioned formula Me designates a metal atom, preferably an alkali atom, for example, a sodium atom or a potassium atorn. Hlg is a chlo'rine, bromine or iodine atom.

In accordance with Method C a compound of the formula XV reacts with a compound of the formula XVI. In the latter formula X designates a chlorine, bromine or iodine atom or a ketoor aldehyde-oxygen atorn.

According to Method D into compounds of the formula XIX there is introduced the group R where it clesignates a lower alkyl group, by reaction with a compound of the formula R Hlg, wheren Hlg designates bromine or chlorine, or with dimethyl ordiethyl sulphate, if R represents a methyl or ethyl group respectively.

In accordance with Method E compounds are produced, wheren R; is a hydroxy gronp, by hydrogenation of a compound of the formula XX.

The details of the Methods A to E are described hereinafter.

Method A.

This method is carried out in a manner known, in principle, for the esterification of an alcohol with an acid, an ester or an acid halide. The reaction takes place, preferably with an acid halide. The reaction may be carried out with the reaction components as such, preferably in substantially equimolar quantities, but it is advisable to carry out the reaction in the presence of a solvent. an acid halide, preferably the chloride, the solvent may be a liquid hydrocarbon, for example, petroleum ether, hexane, heptane, octane, an aromatic hydrocarbon, or exarnple benzene or toluene, furthermore tetrahydrofurane and various other organic solvents, for example ethers such as diethyl ether, diisopropylether, furthermore acetone, chloroform or carbon tetrachloride. reaction may take place at room temperature, but also by heating the reacton mixture, the maximum tempera- Further in these formulae R designates If a compound of the formula I reacts with The ture being the boiling point of the reaction mixture. It is not necessary to add an acid binder to the reaction mixture, since one of the starting substances, i.e. the compound of the formula I, is available as a free base and binds the hydrogen halide set free. The reaction is performed fairly rapidly, i.e. after about 2 to 3 hours.

With the reaction of compounds of the formula I with an acid of the formula IIa Water is produced. For this reason it is interesting to carry out the reaction so that the water produced is withdrawn directly from the reaction mixture. It is therefore advisable to carry out the reaction in a solvent boiling at a fairly high temperature, for example a solvent boiling at a temperature over 70 and distilling azeotropically with water. Such solvents may be benzene, toluene or xylene. As a rule, the duration of the reaction is longer than with the use of an acid halide of the formula IIc.

In accordance with Method A the compounds according to the invention may alsu be obtained by reacting a compound of the formula I with an ester of the formula IIb, preferably a methyl or ethy] e'ster. Although this esterification method is suitable, in principle, it is less important in the present case for practical purposes, since the alcohols of the formula I, which can be synthetized =only with some difficulty, must be available in an excess quantity to terminate completely a reaction with an ester of the formula IIb. If, nevertheless, this reaction is carried out, it is advantageous to proceed so that the produced alcohol is remoVed, for example by distillation. In this case the excess quantity of the alcohol of the formula I may be chosen to be smaller.

In accordance with the aforesaid methods compounds may be produced in which R is a hydroxy-group; In this case it is important, however, that in the starting substance of the formula I, R should designate either a benzylated hydroxy group or a keto group. After the termina-tion of the esterification either the benzyl group is separated out by the catalytic hydrogenation or the keto group is converted into a hydroxy group by reduction, for example also by catalytic hydrogenation.

The compounds of the formula I which are sub stances not descrbed hit-herto, may be produced in various ways known per se for the production of substituted amino alcohols.

The starting material is, for example, a substituted aralkyl compound of the formula III, which is caused to react with an amino alcohol of the formula IV. The substituted aralkyl compound is, for example, an aralkyl halogenized in the aliphatic part, which aralkyl group may contain, moreover, a keto group in the alkyl portion. The amino alcohol is, for example, ethanol amine, propanol amine.

In accordance with a second method of producing the amino alcohols of the general formula I the starting material is a substituted aralkyl amine of the formula V. This compound of the formula V is reacted with, for example, a half-ester half-acid halide, pre f erably the acid chloride of the formula VI. In this formula Y is a divalent, branched or nonbranched alkylene radical with a chain of 0 to 7 carbon atorns, R is an aliphatic radical, for example, a methyl or an ethyl group. Thus half-ester half-acid amide of the formula VII are produced. These half-ester half-acid amides may be reduced into the compound of the formula I with the aid of organic metal compounds, for example those containing two different metal atoms, for instance lithiumaluminium hydride or sodium-boron hydride.

In acco'rdance with a fur=ther method a compound of the formula V is causd to react with a halide alcohol of the formula VIII. A variant of this method consists in that the starting material is not a halide alcohol, but a halide aldehyde or a halide ketone, this requiring afterwards a reduction into alcohol. According to a further method an amine of the formula V reacts with an epoxide, for example ethylene oxide. This method is very suitable for the production of hydroxy amines.

A reaction of a different kind for the production of amino alcohols of the formula I consist in the catalytic reduction of a keto or an aldehyde alcohol with amines of the formula V. If desired, the latter group of compounds may be a diketone or a dialdehyde, bui: this implies the risk that both the ca-rbonyl groups react each with an amino group. The catalytic reduction may, as is known, be carried out under the action of a metal catalyst, for example, platinum, palladium or Raney nickel.

The method of catalytic hydrogenation may, as an alternative, be carried out by starting from aralkyl ketones of the formula IX, which are converted in the presence of amino alcohols of the formula X, by catalytic hydrogenation, into amino alcohols of the formula I.

Method B The compounds according to the invention may also be produced by reacting a compound of the formula XII with a compound of the formula XIII. In these formula XII contains, between the nitrogen atom and iodine atom and Me is a metal atom, for example a potassium atorn or a sodium atom. If a compound of the formula XII contains, between the nitrogen atorn and the halogen atom, an alkylene chain of 4 or 5 carbon atoms, the re is a risk of ring closure, in which the halogen atom reacts with the nitrogen atom. Therefofe this method is less suitable for the use of these starting materals.

With Method B the starting materal is preferably the free base. The starting material may also be a salt of the free amine, for example the hydrochloric acid salt, but in this case it is advisable to react one moll of the salt of the compound of formula XII with 2 mols of the compound of the formula XIII or, and this is a different possibili-ty, with one equivalent of the compound of formula XIII and an equivalent of lye, for example, diluted, aqueous sodium or potassium hydroxide.

As a solvent for the reaction of Method B use may be made of dlerent organic solvents, for example, chloroform, acetonitrile, aromatic hydrocarbons such as .benzene toluene or xylene; aliphatic hydrocarbon radicals are less suitable, since the reaction constituents are too little soluble herein. It is further advisable to carry out the reaction at the boiling temperature of the solvent. A normal reaction temperatre lies approximately between 70 and 130 C. The duration of the reaction is fairly long and, at the given temperature, it lies between approximately 50 and hours.

The compounds of the formula XII may be produced by reacting the corresponding alcohols with phosphorpentachloride, thionylchloride, phosphor tribromide or thionylbromide.

If the group R, is a hydroxyl group, it may be halogenized also in the said reaction. This may be avoided by benzylating the group R or by acylating it previously, for example by acetylating it.

This halogenation may, if desired, be c'arried out without using a solvent. Better results are often obtained when carrying out the reaction in the presence of a solvent.

Suitable solvents are: carbon tetrachlorde, benzene, toluene, in general indifierent olvents. A further methcd of producing the compounds of formula XII consists in that compounds of formula V are reacted with compounds of formula XIV. Preferably, at least one equimolar quantity of a compound of formula XIV is used. The compound of the formula V is preferably available in the form of the free base. The hydrogen halide produced during the reaction is bound by the produced reaction substance.

In the description of Method B reference has been made to the risk of cyclization. The risk thereof also exists in the present case, if a compound of the formula phosphoroxy chloride,

XIV contains, between the carbon atoms to which the halogen atoms are bound, two or three further carbon atorns.

Method C In order to obtan the compounds according to the invention the last step of esterification with a nuclear substituted benzoylhalide, which may, if necessary, be followed by a further step, for example the catalytic separation of benzyl groups or the reduction of any keto groups, may be replaced by the production of substituted benzoyl esters of the formula XVI, which are reacted with compounds of the formula XV. In these formulae R to R and Y designate the groups and atoms referred to above, whereas X is a halide atom, for example a chlorine, bromine or an iodine atom or a double-boncled oxygen atom.

If X is a halogen atom, the reaction is preferably carried out so that 1 mol of the compound of the formula XVI reacts with at least 1 mol of the free base of the formula XV. Use is preferably made of 2 equivalents of the last-mentioned compound, 1 mol acting as an acid binder. As an alternative, 1 equivalentof the compound XV and furthermore an equivalent of acid binder, for example a tertiary amine such aspyridine, collidine or triethanolamine may be used.

The reaction between a compound of the formulae XV and XVI (X=halogen) takes place preferably in, the presence of a solvent. To this end use may be made of aromatic hydrocarbons, such as benzene, toluene, xylene, furthermore .chloroform, carbon tetrachloride, acetone, acetonitrile.

Also ethers, such as diethyl ether, diisopropyl ether, may be used. Moreover, in principle, aliphatic hydrocarbons may be used as a solvent. These compounds are, however, very little polar, so that the coupling reaction is performed usually very slowly.

It is advisable to carry out the reaction at a higher temperature. It is simplest to carry out the reaction at the boiling temperature of the solvent. A temperature lying between 40 and 130 C. provides suitable results.

The duraton of the reaction varies with hte choice of the solvent and the reaction temperature. In this connection theduration of the reaction may vary between. a few hours and about two days. If in the formula XVI X is a ketoor an aldehyde-oxygen atom, the reduction preferably takes place with hydrogen and a metal catalyst. This catalytic hydrogenation may be carried out with a noble metal, for example, platinum, palladium or Raney nickel as catalysts. It is little advisable to use, as starting material, compounds of the formula XV, in which R does not represent a hydrogen atom; if R is an alkyl group, high temperatures and pressure must be used during the catalytic hydrogenation, for example temperatures between 100 and 200 and pressures between 10 and 100 atmospheres. If desired, after ter-mination of the hydrogenation, by alkylation, the group R if it represents an alkyl-group, may be introduced. The present method is less suitable for reactions between those products in which the compounds of the formula XVI contain a carbon chain with less than 3 carbon atoms between the oxygen atom of the ester group and the oxygen atom X.

If such compounds were nevertheless used, this implies the complication of hydrogenolysis of the ester.

If platinum or palladium is used as a catalyst, the hydrogenation may be carried out at,normal pressure and temperature, preferably in an acid medium -or, if necessary, in a neutral or a weak alkaline medium. The reaction is preferably carried out in the presence of diluted hydrochloric acid, acetic acid or sulphuric acid. If desired, the free base is subjected to a catalytic hydrogenation with a compound of the formula XVI.

The hydrogenation with Raney nickel is preferably carried out in an alkaline medium and at a higher temperature and pressure. In order to obtain the alkaline medium it is not necessary to add lye. It suflices to work with the freebase. As a rule, it is advs-able to choose the pH of the reaction medium between 8 and 11. If the free base is not sufficiently alkaline, the additon of diluted alkali, for example sodium hydroxide or potassiurn hydroxide may increase the pH to the said value.

The temperature is preferably chosen to be between 60 C. and C., and the pressure between 1 and 10 atmospheres; the reaction may be carried out in the presence of a non-self-reducing solvent, which will preferably -be a lower aliphatic alcohol, for example ethanol, propanol, isopropanol or amyl alcohol, or mixtures thereof with water, the reaction mixture having -to be worked up so that ester interchange cannot occur. During the reduction ester interchange may sometirnes occur. In this case use shuold be made of a further diluted alcohol as a solvent. As an alternative, the catalytic hydrogenation may be carried out in water or in acetic acid or in mixtures thereof.

It should be noted that, if the staring substance of the formula XV contained a benzyl'oxy group or a keto group, these functions are converted during the coupling reaction into a hydroxy group.

Compounds of the formula XVI may be produced in different ways. For example a compound of the formula II is esterified with a halogen alcohol of the formula VIII. The esterifying reaction takes place onder conditions which are otherwise the same as referred to above for esterification reactions.

In order to produce compounds of the formula XVI, a compound of the formula II may be esterified with a dialcohol of the formula XVII. Thus compounds of the formula XVIII are obtained. The esterification may take place again in the manner described above. It is advisable to carry out the reaction with at least 1 equimolar quantity of the dialcohol in order to avoid that compounds are obtained in which the two alcohol groups are esterified. The hydroxy esters obtained may then be converted by halogenation agents capable of replacing the hydroxy-group by a halogen atom, into a compound of the formula XVI. The halogenation agents may be thionylchloride, phosphorpentachloride, phosphoroxychloride, phosphortribromide and thionylbromide.

In accordance with a third method compounds of the formula XVI may be produced by esterifying a compound of the formula XIII, preferably an alkali salt, for example the sodium salt, with an aliphatic dihalogen compound of the formula XIV. The reaction is again carried out preferably with at least l equimolar quantity of the dihalogen compound in order to avoid that also the second halogen atom participates in the esterification. The halogen compound is preferably the dichloro or dibromo compound.

Compounds of the formula XVI, in which X represents a double-bonded oxygen atom, may be produced by esterification of an acid or an acid halide of the formula II with an aldehyde or a keto alcohol. The esterification may, as an alternative, take place wtih a dialcohol, after which -the nonesterified alcohol group is oxidized into an aldehyde or a keto group. In the latter case the esterification takes place, preferably, with at least 1 equimolar quantity of the dialcohol. According to a third method the keto -or aldehyde esters are obtained by esterifying a compound of the formula XIII, preferably an alkali salt thereof, witha halogen ketone or a halogen aldehyde.

Method D In accordance with this method a compound of the formula XIX reacts with a halogen alkyl of the formula HlgR for example ClR If R is a methyl or an ethyl group, the desired compound may also be obtained by reacting a compound of the formula XIX with dimethyl or diethyl sulphate. The reaction with a compound of the formula R Hlg is preferably carried out with at least 1 mol of the free base of the formula XIX. Use is preferably made of 2 rnls of this compound to bind acid set free during the reaction. As an alternative, 1 mol of the free base may be used and 1 mol of an acid binder may be added to the reaction medium, for example a tertiary amine, such as pyridine, collidine or triethanol amine or an inorganic carbonate such as sodiumor potas sium-carbonate. As a solvent with this alkylatin reaction may be used aromatic hydrocarbons, for example benzene or toluene, furtherrnore chloroforrn, carbon tetrachloride, organic ethers, for example diethyl or diisopropyl ethers, if desired even alcohols such as ethanol, propanol, isopropanol or butanol, provided the reaction conditions are chosen to be such that ester interchange cannot occur. If desired, tetrahydrofurane or dioxane may be used as solvents. The temperatures at which this reaction is preferably carried out vary between 40 and 120. The reaction may take place at room temperature, but preferably at the boiling point of the solvent. The duration of the reaction, which varies also with the solvent used and the temperature of the reaction, is from a few hours to goed one day.

If use is made of a dialkylsulphate as an alkylation agent, use is preferably made of an aqueous solution, whilst simultaneously with the dialkylsulphate lye is added, care being taken that the reaction mixture reacts invariably alkaline.

Method E It should finally be noted that the methods describedunder A to E serve as examples of the manner in which the compounds according to the invention may be produced. The number of methods or combinations thereof is not exhausted by this description. Neither methods described, nor the examples to be mentioned hereinafter are ntended to restrict the protectve rights clamed.

EXAMPLES When reference is made in these examples to alcohol and ether, 96% ethanol and di-ethyl ether respectively are meant, unless it is stated otherwise.

I. 2-(3,4'-dimethoxy-benzoylbxy) -[Nbutyl-2-(4"'- methoxyphenyl) ethylamno]-hexane (a) 5-butylamino-hexanol-Z.A solution of 43 g. (0.37 mol) of 5-ketohexanol-Z (produced as described in Doklady Akad. Nauk. S.S.S.R. 88, 845 (1953)), 33 g. (0.45 mol) of butylamine in 150 m1. of alcohol was hydrogenated at room temperature under atmospheric pres sure with platinum as a catalyst. When the absorption of hydrogen terminated, the reaction mixture was filtered ofi, the filtrate was acidified with concentrated hydro chloric acid. The alcohol was evaporated and the residue was -dissolved in water. This solution was washed with ether, then rendered alkaline and extracted three times with ether. The etheral extracts were dried on Na SO filtered, the ether evaporated and the residue was distilled in vacuo. The yield was 20 g. (31%). Boiling point 65 to 80 C./ 0.7 mm. Equivalent weight 178 (calculated 173).

(b) 5 [N-butyl 2'-(4"-methoxyphenyl)ethylamino] hexanol-2.A mixture of 19 g. (0.11 mol). of 5-butylaminohexanol-2 and 8 g. (0.038 mol) of 4-rnethoxyphenyl- 8 ethylbromide (produced as described in I. Org. Chem. 9, 250 (1944)) was heated at to C. for 8 hours. After cooling 25 m1. of dry ether was added and the mixture was left for 20 hours. Then 25 ml. 0 water was added and the aqueous layer was separated off. The ether layer was washed once with 10 ml. of water. The collected aqueous layers were extracted twice with 10 ml. of ether. These thereal extracts were unitod with the thereal layer and dried on Na SO The aqueous layer was found, by titration, to contain 0.037 equivalent Brions. The solution in ether was filtered, the ether evaporated and the residue distilled in vacuo. The yield was 6.5 g. (57%). Boiling point 158 to 162 C. Eq. weight 310 (calculated 307).

(c) 2 (3,4' dimethoxy benzoyloxy) 5 [N-butyl- 2"-(4"-methoxyphenyl) ethylamno] hexne.-To a solution of 3.1 g. (0.01 mol) of 5-[N-butyl-2-(4"-methoxy phenyl)ethylamino] hexanol-2 in 80 ml. of dry benzene was added 2.1 g. (0.01 mol) of 3,4dimethoxybenzoylchloride and this solution was boiled for 6 hours. After the evaporation of the 'benzene, an -oil was obtained, which was dissolved in 15 m1. of 30% alcohol, rendered alkaline with 5 ml. of concentrated NH,OH and after the dilution withwater to 100 ml. it was extracted twice with 30 ml. of ether. The ethereal extracts were dried on Na SO filtered and the ether was evaporated. The oil-like residue had a weight of 3.3 g. (=70%'). Eq. weight 472 (calculated 471). Ultraviolet absorption spectrum: max=262.5 mu e, max 7850; max=285 ma 6 max=5,200.

II. 1-(3,4'-dimethoxy-benzoyloxy) 5-[N-methyl-Z- (4"'-amnophenyl) ethylamno] hexane-dihydrochlorde.

(a) 5-methylamno-hexanol-I.The production took place in accordance with the method described sub Ia. Instead of using lplatinum, use was made of Raney nickel as a catalyst. Since, after the first d-istillation, the equivalent weight was found to be too high, the substance was purified by dissolving the hydrochloride in water; this solution was washed with ether and then rendered alkaline, after which it was extracted with ether. The ethereal extracts were dried on Na SO filtered, the ether was evaporated and the residue was again distilled in vacuo. The yield was 30%. Boiling point 80 to 83 C./0.8/mm. Eq. weight (calculated 131).

(b) 5-[N-mezhyl-2-(4"ntrophenyl)ethylamino] hexanol-I.A solution of 7 'g. of S-methylamino-hexanol-l (0.05 mol), 11.5 g. (0.05 mol) of 2-(4-nitrophenyl) ethylbromide (produced as described in I. Am. Chem. Soc. 62, 1436 (1940)) and 7.5 g. (0.05 mol) of triethanolamine in 100 m1. of absolute alcohol was boiled for 10 hours. Then the alcohol wasevaporated and to the residue was added 50 m1. of water and 200 ml. of ether. The ethereal layer was washed twice with 25 ml. of water. The aqueous layer was found, by titration, to obtain 0.05 equivalent Br ions. The ethereal layer was then extracted twice with 20 ml. of 0.15 N hydrochloric acid. The aqueous solution thus obtained was rendered alkaline by 5 m1. of 50% sodium hydroxide solution and extracted twice with 50 m1. of ether. The ethereal extracts were dried on Na SO filtered and the ether was Eq. weight 9 III. 1 (3',4' dmethoxy benzoyloxy) 4 [N ethyl- 1" methyl 2" (4"' methoxyphenyl)ethylamno] butane hydrochlorcle half an hour, whilst stirring and cooling in a waterbath of room temperature, a solution of 24.7 g. (0.15 mol) of 3-carbaethoxy-propionylchloride (see for its producton: I. Am. Chem. Soc. 60, 402 (1938)) in 150 ml. of dry benzene. The mixture was lboiled, whilst stirring, for 3 hours, cooled and the deposit formed was filtered of and washed with ether. The ether and the benzene were evaporated from the filtrate and the residue was distilled in vacuo. The yield was 46 g. (95%). Boiling point 172 to 175 C./0.1 mm.

(b) 4-[N-ezhfl-Imethyl-2-(4"-methoxyphenyl)ethylamino]butanol-Z.A solution of 46 g. (0.15 mol) of NN-ethyl-1-methyl-2'(4"methoxyphenynethyl 3-carbaethoxy-propionamide in 200 ml. of dry ether was added, within 30 minutes, to a solution of 20 g. (0.5 mol) of lithium-aluminum hydride in 500 ml. of dry ether. The mixture was then boiled for 20 hours. The reaction complex was decomposed with water and the deposit obtained was filtered off and washed with ether. The solution in ether was dried on sodium sulphate, filtered, the ether evaporated and the residue was distilled in vacuo. The yield was 31 g. (78%). Boling point 158 to 163 C./0.08 mm. Eq. weight 257 (calculated 265).

(c) 1 (3,4 dmethoxy-benzoyloxy) 4 [N-ethyl-l" methyl Z"-(4'-meth0xyphenyl)ethylamino]butane hydrochloride.-The production was carried out by the method descrbed sub Ic by esterifying the compound descrbed in the preceding paragraph with 3,4-dimethoxybenzoylchloride. The yield was 88%. Melting point 97 to 102 C. Chlorine content 7.68% (calculated 7.66% U.V. absorption spectrum: Mrnax=262.5 mu, e max= 11,700; ;;max=285 ma, e rnax=6,000.

After crystallisation from methylethylketone the melting point was raised to 105107 C.

Analyss.-Foundz C 74.71%, H 7.85%, N 2.97%.

Calc.: C 64,73%, H 7.83%, N 3.02%.

(a) 1-(3',4'-dimethoxyphenyl) 2-(N-ethylamno)propane.The production took place in accordance with the method des cribed sub Ia by hydrogenating a mixture of 1-(3,4dimethoxyphenyl)propanone-Z (J. Am. Chem. Soc. 66, 26 (1944)) and ethylamine with platnum as a catalyst. The yield was 81%. Boiling point 162 to 165 C./13 mrn. Eq. weight 229 (calculated 223).

(b) NN-ethyl-I' methyl 2-(3"4"dimethoxyphenyl)ehyl 3 carbaethoxyproponamde. The production took place in accordance with the method described sub IIIa by reacting the compound described in the preceding paragraph with 3carbaethoxy-propionylchloride. The yield was 100%. The nondistilled product was used for the following reaction:

(c) 4-[N-ethyl-1IJnethyl--(3"4"-dmethoxyphenyl) ethylamz'no]bucmolJ.-The production took place in accordance with the method described sub IIIb by reducing the compound described in the preceding paragraph with a solution of lithium-aluminium hydride in ether. The yield was 70%. Boiling point 165 .to 168 C./0.08 mm. Eq. weight 297 (calculated 295).

(d) 1 (3,4 dmethoxy benzoyloxy)-4-[N-ethyl-I- methyl-2",3",4dmethoxyphenyl) ethylamino]butane. The production was carried out in accordance with the method described sub Ic by esterifyng the compound described in the preceding paragraph with 3,4-dimethoxybenzoylchloride. T he hydrochloride would not crystallize from acetone, methyl-ethylketone, alcohol and mixtures of these solvents with ether. By dissolving the hydrochloride in water rendering ths solution alkaline with ammonia and extracting it with ether, the free base was isolated. The yield was 93%. Eq. weight 460 (calculated 459). U.V. absorption spectrum: Mmax=262 II1,LL, e max=12000; Mrnax=287 mu, e max=7,320.

(a) J-(3'4'-dimethoxy-benzoyloxy)-6-brom-hexane. A suspension of 20.5 g. (0.1 mol) of a sodium salt of 3,4- dimethoxy-benzoic acid in a solution of 30 g. (012 mol) of 1.6-dibrom-hexane in 250 m1. of dry acetonitril was boiled for hours. After cooling the deposit was filtered off. The acetonitril was evaporated in vacuo frm the filtrate and the residue was distilled in vacuo. The yield was 14.5 g. (42%). Boiling point 202 to 205 C./0.5 mm. Bromine content 25.8% (calculated 23.2 With the distillation 16.5 g. of 1.6-dibrorn-hexane was reobtained.

(b) 1 (3,4' dz'methoxy-benz0yloxy)-6-[N-ethyl-I- methyl-2"-(4methoxyphenyl)ethylamno]hexane hydr0ch0ride.-A solution of 15.5 g. (0.08 mol) of N-ethyllrnethyl2(4methoxyphenyl)ethylamine and 13.8 g. (0.04 mol) of 1-(3,4'-dmethoxybenzoyloxy)-6-bromhexane in 100 m1. of dry acetonitril was boiled for 100 hours. The acetonitril was evaporated in vacuo and to the residue was added 75 ml. of dry ether. The deposit was filtered oi and the ether evaporated from the filtrate. The residue was dissolved in 20 m1. of 2 N-alcoholic hydrochloric acid and the alcohol was evaporated in vacuo. The residue was crystallized from a mixture of 15 m1. of methyl-ethylketone, and 30 ml. of ether. The yield was 15.5 g. (77%). Melting point 82 to 93 C. Chlorine content 7.8% (calculated 7.2%). U.V. absorption spectrum: Mmax=262 111/L, e max= 12,400, Mmax=285 m e max=6,300.

After crystallisation from a mixture of methylethylketone and ether the melting point was raised to 95 to 98 C. Chlorine content 7.2% (calculated 7.2%).

Analysis.-Foundz C 65.84%, H 8.20%, N 3.06%. Calc.: C 65.70%, H 8.17%, N 2.84%. This compound may be produced in a different manner.

(al) I-brom0-6-[N-ethyl-l"methyl-Z"-(4"-methoxy phenyl)ethylamno]hexanehydrobromde.-A solution of 19.3 g. (0.1 mol) of N-ethyl-l-methyl2(4"methoxyphenyl)ethylamine and 24.4 g. (0.1 mol) of 1,6-dibromhexane in 250 m1. of absolute alcohol was boiled for 4 hours. After cooling the reaction mixture was filtered off and the alcohol was evaporated from the filtrate. To the residue was added 100 ml. of acetone and after one day in the refrigerator the deposit was filtered 0 and dried. The yield was 21 g. (48%). Bromine content (ionogeneous) 19.7% (calculated 18.3%).

(bl) 1-(3',4dmethoxy-benzoyloxy) -6[N-ethyl-l"- methyl 2"-(4'-methoxyphcnyl)ethylamin0]hexane hydrochlarde.-A suspension of 12 g. (0.05 mol) of the Sodium salt of 3,4-dimethoxy-benzoic acid and 11 g. (0.025 mol) of the hydrobromide described in the preceding paragraph in 250 m1. of dry acetonitril was boiled for 100 hours and the acetonitril was then evaporated in vacuo. To the residue was added 100 m1. of water and 200 ml. of ether; the ethereal layer was isolated and the aqueous layer extractecl once with 50 m1. of ether. The ethereal extracts were collected, washed twice with 50 ml. of water, dried on sodium sulphate and filtered. To the filtrate was added 25 m1. of 2 N-alcohol hydrochloric acid and the deposit was filtered off. The deposit was crystallized from a mixture of 10 ml. of niethylethylketone and 20 m1. of ether. The yield was 6.7 g. (50%). Melting point 93 to 96 C. Chlorine content 7.4% (calculated 7.2%

(a) N,N ethyl 2 (4 ethoxyphenyl)ethyl 3-carbaethoxy-propz'onamde.-The production was carried out by the method described sub IIIa by reacting N-ethyl-2- (4-ethoxyphenyl)ethylamine with 3-carbaethoxy-propionylchloride. However, in this case not the amine itself, but triethylamine wasused as an acid binder. The crude reaction product (48 g.=100%) was used directly for the following reaction.

(b) 4 [N ethyl-2-(4"-ethoxyphenyl)ethylamino]- butanol-J .The production was carried out by the method described sub IIIb by reducng the compound described in the Preceding paragraph with lithium-aluminium hydride. The yield was 36%. Boiling point 155 to 157 C./0.1 mm. Eq. weight 270 (calculated 265).

(c) 1 (4 methoxy-benzoyloxy)-4-[Nethyl2"-(4"'- ethoxyphenyl)ethylamno] butane hydrochloride.-The production took place by carrying out the method descrbed sub Ic by esterifying the compound described in the preceding paragraph with 4-methoxy-benzoylchloride. The yield was 74%. Melting point 103 to 104 C. Chlorine content 8.20%. (calculated 8.14%). U.V. absorption spectrum: =258 m t e 17,800.

Anaylsis.Found: C 66.05%, H 7.99%, N 3.19%. Calc.: C 66.19%, H 7.87%, N3.22%.

V11. 1 (4 methoxy-benzoyloxy-4-[N-ethyl-l"-methyl- 2"-(4-ethoxyphenyl ethylamno] butanehydrochlaride 2-(4" ethoxyphenyl)ethylamino] butane hydrochlrde.-The production took place by carryin-g out the method described sub Ic by esterifying the compound described in the preceding paragraph with 4-methoxybenzoylchloride. The yield. was 80%. Melting point 83 to 86 C. Chlorine content 7.93% (calculated 7.89%). U.V. absorption spectrum: =258 mu, e =l7,40.

Analysis.-Fondz C 64.67%, H 8.11%, N 3.07%. Calc.: C 66.80%, H 8.07%, N 3.11%.

VIII. 1 (4ethoxybenzoyloxy-4-[N-ethyl-l-methyl-2" (4"'-ethoxyphenyl) ethylamno] .butane hydrochloride The production took place by carrying out the methoddescribed under Ic by esterifying the c-ompound described VIIc of 4-[N-ethyl-1-methyl-2-(4-ethoxyphenyl)ethylamino butanol-l with 4-ethoxybenzoylchloride. The yield was 87%. Melting point 113 to 114 C. Chlorine content 7.50% (calculated 7.65%). U.V. absorption spectrum: =257. m e 17,300.

Analyss.-Found: C 67.63%, H 8.47%, N 3.08%. Calc.: C 67.37%, H 8.27%, N 3.03%.

IX. I-(4'-hydroxy-benzoyloxy)-4-[N-ethyl 1" methyl- 2" (4 ethoxyphenyl)ethylamino] butane hydrochloride (a) 1-(4-benzyloxy-benzoyloxy)-4-[N-ethyll"-methyl- 2" (4 ethoxyphenyl)ethylamno] butane-hydrochlride.The production took place by carrying out the method described sub Ic by esterifying the compound described in the paragraph VIIc of 4-[N-ethyl-l'-methyl-Z'- (4-ethoxyphenyl)ethylamino] butanol-1 with 4-benzyl- 12 oxy-benzoylchloride. The yield was 86%. Melting point 114 to 117 C. Chlorine content 6.73% (calculated 6.78%

(b) 1 (4-hydroxy-benz0yloxy)-4-[N-ethyl-I-methyl- Z"-(4"'-ethoxyphenyl) ethylamino] butane-hydrochlorde. 5.23 g. (0.01 mol) of the compound described in the preceding paragraph was dissolved in 75 m1. of alcohol. Thereto was added a prehydrogenated, acid-tree palladium catalyst, obtained from 150 mg. of palladium chloride and 750 mg. of decolouring carbon and hydrogenated. After the calculated quantity of hydrogen and been absorbed, the catalyst was filtered ofi and the filtrate was thckened to dryness in vacuo. The residue was crystallzed from 25 ml. of acetone, filtered 0 and dried. The yield was 3.55 g. (82%). Meltng point 129 to 130 C. Chlorine content 8.14% (calculated 8.18%). U.V. absorption spectrum: =259 m;r, e =17,100.

Analysis.-Found: C 66.41% H 8.07%, N 3.20%. Calc.: C 66.49%, H 7.91%, N 3.24%.

X. I-(4'-methoxy-benzyloxy) 4 [N-ethyl 1" methyl- 2"-(3'",4'5"' trimethoxyphenyl)ethlamino] butanehydrochlorde (a) N,N-ethyl-l-methyl-Z-(3,4",5"-trimethoxylphenly)ethyl-3-carbaethoxyproponamde. The production took place by carrying out the method described sub IIIa by racting N ethyl 1' methyl-2'-(3"4",5-trirnethoxyphenyl)ethylamine with 3-carbaethoxypropionylchloride. However, not the amine itself, but triethylamine was used as an acid binder. The conversion took place quantitatively. The crude product was used for the following reaction.

(b) 4 [N-ethyl 1-methyl-Z-(3",4,5"-rimeth0xy phenyl)ethylamino] butanol-1.The production was carried out by the method described sub llb by reducing the compound described in the preceding paragraph with lithium-aluminiumhydride. The yield was 45%. Boiling point 182 to 186 C./0.05 mrn. Eq. weight 318 (calculated 325).

(c) 1 (4-methoxy-benzoyloxy)-4-[N-ethyl-l"-metlzyl- 2" (3',4'5 trimethoxyphenyl)ethylamno]butane. The production was carried out by the method described sub Ic by esterifying the compound described in the preceding paragraph with 4-methoxy-benzoylchloride. The yield was 61%. U.V. absorption spectrum: =254 to 258 nm, s 17,300. Eq. weight 470 (calculated 459).

XI. 1-(3',4',5-trimethoxy-benzoyloxy)-4-(N ethyl 2"- phenyl ethylamz'no)-butane.

(a)N,N-ethyl-2'-phenylethyl 3carbaethoxy propionicamde.-To a soluton of 33.7 g. (0.226 mol) of Nethyl 2-phenylethylamine in m1. of dry ether was added, within 15 minutes, while stirring and cooling in a water bath of room temperature, a solution of 18.4 g. (0.112 mol) of 3-carbaethoxy-propionyl chloride (for the production thereof see: I. Am. Chem. Soc. 60, 402 (1938)) in 50 m1. of dry ether. The mixture was boiled, while stirring, for two hours, cooled and the precipitation produced was iltered 0 and washed with ether. The ethereal solution was dried on sodium sulphate, after having been washed twice with 40 ml. of water. After the filteration the ether was evaporated and the residue was dstilled in vacuo. The yield was 25 g. (64%). Boilng point 172 to 175 C./0.1 mm.

(b) 4 (N ethyl-Z'phenylethylamno)butanol-I.A solution of 25 g. (0.09 mol) of N,N-ethyl-2-phenylethyl- 3-carbaethoxy-propionic amide in 100 m1. of dry ether was added, within 25 minutes, while stirring, to a solution of 15 g. 0.4 mol) of lithium-aluminium hydride in 350 m1. of dry ether. The mixture was boiled, while stirring, for 16 hours. The reaction mixture was decomposed with water and the precipitation produced was filtered of]? and washed with ether. The ethereal soluti'on was dried on sodium sulphate. and filtered ol. After the evaporation 13 of the ether, the residue was distilled in vacuo. The yield was 15 g. (80%). Boiling point 132 C./0.5 mm. Eq. weght 221 (calculated 221).

(c) 1 (3',4,5' trz'methoxy benzoyloxy) 4 (N- ethyl-2"-phenyl-ethylamino) butane.-To a solution of 4.4 g. (0.02 mol) 4-(N-ethyl-2-phenylethylamino) butanol-l in 50 ml. of dry benzene was added, while cooling with water of room temperature, within 20 minutes a solution of 6.9 g. (0.03 mol) 34,5-trimethoxy-benzoylchloride (I. Am. Chem. Soc. 73, 144 (1951)) in 40 m1. of dry benzene. After the addition the reaction mixture was boiled for three hours. After evaporation of the benzene the residue was dissolved in acetone. Thus a small quantity of precipitation was obtairred, which was filtered o. The acetone was evaporated from the filtrate and the residue was dssolved in 60 ml. of water. The aqueous solution was alkalized with 1 N ammonia and extracted three times with 50 m1. of ether. The ethereal solution was dried on sodium sulphate and filtered oi. After the evaporation of the ether, an oil was obtained. T he yield was quantitative. Equivalent weight 417 (calculatecl 415). Methoxyl content 22.43% (calculated 22.41%). Ultraviolet absorption spectrum: ,,.=265 m e,=10380. Spasm. act. 4 to 5.

Production the bimxalate.-The free base of 1-(3', 4',5'-trimethoxy-benzoyloxy) 4-(N-ethyl-2"phenylethylamino)butane and oxalic acid were dissolved in equimolar quantities in acetone. After the addition of ether a crystallinic substance was precpitated. Melting point 120 to 123 C. (sintering at 118 C.). 0.5 g. was crystallized from 3 mm. of alcohol. Melting point 123 to 125 C. After another crystallization from alcohol the melting point was 127 to 129 C.

AnaIysis.-Foundt C 62.04%, I-I 6.96%, N 2.98%,

3.07%, 2.82%, 2.93%, 0CH 18.16%. Calc.: C 61.78% H 6.93%, N 2.77%, OCH 18.42%.

Producton of the hydrochlorde.2.4 g. of the free base was dissolved in absolute alcohol and an equimolar quantity of 0.27 N alcoholic hydrochloric acid was added. T he alcohol was evaporated and the residue dissolved in acetone. To this solution was added ether until turbidity was produced. After a stay in a refrigerator (5 C.) crystallization occurred. The precipitate was filtered ofi". The weight was 2.8 g. Chlorine content 7.87% (calculated 7.86%). Melting point 103 to 104 C. After crystallization from a mixture of 5 m1. of methylethylketone and m1. of ether, 2.2 g. of the substance was obtained; melting point 106 to 108 C. U.V. spectrum: =265 to 267.5 m;r, e 10,400.

Analyss.-Found: C 63.61%, H 7.52%, N 3.00%. Calc.: C 63.79%, H 7.53%, N 3.11%.

(a) N,N benzyl 2 phenylethyl 3 czzrbaethoxyproponc amde.To a solution of 21.1 g. (0.1 mol) of N-benzyl-2-phenylethylamine and 7.9 g. (0.1 mol) of dry pyridine in 75 ml. of dry ether was added, within 20 minutes, while stirring, a solution of 16.5 g. (0.1 mol) of 3carbaethoxy-propionylchloride in 25 ml. of dry ether. During the addition a further 125 ml. of dry ether was added to the reaction mixture, since stirring was rendered diflicult by the precipitate produced. After the addition the reactionmixture was boiled, while stirring, for one and a half hours. After cooling the precipitate formed was filtered off and washed with ether. The ethereal solution was washed with 40 ml. of water, dried on Na SO and filtered. The ether was evaporated from the filtrate and the residue was distilled in vacuo. The yield was 27 g. (80% Boiling point 217 to 219 C./0.03

(b) 4 (N benzyl 2 phenylezfhylamno)butanol- I.A solution of 37 g. (0.11 mol) of N,N-benzyl2- phenylethyl-3-carbaethoxypropionic amide in 200 ml. of

14 dry ether was added, within 15 minutes, to a solution of 8.5 g. (0.22 mol) of lithium-aluminium hydride in 300 m1. of dry ether. After the addition the mixture was boiled for 20 hours, while stirring. The reaction mixture was decomposed with water and the precipitate produced was filtered off and washed with ether. The ethereal solution was clried on sodium sulphate and filtered oi. After the evaporation of the ether the residue was distilled in vacuo. The yield was 19.5 g. (65%). Boiling point 185 to 189 C./0.8 mm. Eq. weight 282 (calculated 283).

(c) 1.- (3',4',5 trz'methoxy benzoyloxy) 4 (N- benzyl-2"-plzenylethylamno) butane hydrochloride. To a solution of 8.5 g. (0.03 mol) of 4-(Nbenzyl-2- phenylethylamino)butanol-1 in 40 m1. of benzene was added, while stirring at room temperature, within 15 minutes, 6.9 g. (0.03 mol) of 34,5-trimethoxybenzoylchloride. The reaction mixture was boiled for two and a half hours, while stirring, after which the benzene was evaporated in vacuo. The residue was crystallized from a mixture of 15 ml. of acetone and 15 ml. of ether. The yield was 14 g. (91%). Chlorine content 6.82% (calculated 6.91% After crystallization from acetone, the melting point was 134 to 136 C. U.V. absorption spectrum: l =265 m -e=9,900.

Anayss.-Found: C 67.36%, H 7.02%, N 2.76%, OCH3 18.19%. Calc.: C 67.77%, H 7.01%, N 2.72%, OCH 18.11%. Spasm. act. 3.

X111. 1(3,4,5-trimethoxy-benzoyloxy)-4-(N-ethyl-J"- methyl-2phenylethylamino) buttme hydrochlorde (a) N,N ethyl 1 methyl 2 phenylethyl 3- carbaezhoxy-propionc amz'de.To a solution of 14.2 g. (0.09 mol) of Nethyl-lnethyl-2-phenylamine and 6.9 g. (0.09 mol) of pyridine in 50 ml. of dry benzene was added, within 20 minutes, while stirring, at room temperature, 14.4 g. (0.09 mol) of 2-carbaethoxy-propionylchloride. After the addition the mixture was boiled while stirring, for two hours. After cooling the reaction mixture had added to it m1. of dry ether. The reaction mixture was filtered off, a precipitate being separated out, which, subsequent to drying, proved to have a weight of 10 g. and a chlorine content of 29.1%. The solvent was evaporated from the filtrate, after which the residue was distilled in vacuo. The yield was 19.5 g. (77%). Boiling point 170 to 174 C./0.08 mm.

(b) 4 (N ethyl 1 methyl -2' phenylezhylamno) bumnol-I.A solution of 19 g. (0.065 mol) of N,N- ethyl 1 methyl 2 phenylethyl 3 carbaethoxypropionic amide in ml. of dry ether was added, within 30 minutes, while stirring, to a solution of 8 g. (0.21 mol) of lithium-aluminium hydride in 300 m1. of dry ether. After the addition the mixture was boiled, while stirring, for 20 hours. The reaction complex was, while cooled in an ice bath, decomposed with water and the precipitate formed was filtered off and washed with ether. The ethereal solution was dried on sodium sulphate and filtered off. After the ether had been evaporated, the residue was distilled in vacuo. The yield was 11.6 g. (75%). Boiling point 118 to 122 C./0.1 mm.. Eq. weight 231 (calculated 23 5).

(c) 1 (3',4',5' trimethoxy-benzoyloxy) 4 (N- ethyl-J"-methyl-2"-plzenylethylamino)butane hydrochlorde.-To a solution of 7.05 g. (0.03 mol) of 4(N-ethyl- 1'-methyl-2'-phenylethylamino)butanol-l in 50 ml. of dry benzene was added, within 10 minutes, while stirring, a solution of 6.91 g. (0.03 mol) of 3,45-trimethoxy-benzoylchloride in 50 In]. of dry benzene. Then the reaction mixture was boiled for three hours, while stirring and the benzene evaporated in vacuo. The residue was dissolved in a mixture of 15 m1. of methyl-ethylketone and 15 ml. of ether. The crystals produced were filtered ofr. The yield was 8.4 g. (60%). The substance proved to be very hygroscopic and even after one night of drying in vacuo on phosphorus pentoxicle t proved to contain 15 moisture. Melting point 68 to 74 C. Eq. weight 480 (calculated 465.5). U. V. absorption spectrum:

Spasm. act. 15.

The substance was converted into the free base and the ol was analysed. Eq. weight 428 (calculated 429).

Analysis.Foundz C 69.35, 69.45%; H 8.10, 7.87%; N 3.30, 3.26%; OCH 21.72%. Calc.: C 69.93%, H 8.16%, N 3.26%, OCH 21.68%.

XIV. I (3',4,5' zrimethoxy benzoyloxy) 6 (N- ethyl-2-phenylethylamino hexane (a) 1 (3',4',5' trmethoxy benzoyloxy) 6 bromohexane.-This compound was produced in two ways, which are described in this example under (1) and (2).

( 1) A suspension of 23.5 g. (0.1 mol) of the sodium salt of 3,4,5-trimethoxy-benzoic acid in a solution of 24.5 g. (0.1 mol) of 1,6-dibromohexane in 50 m1. of xylene was kept for 60 hours in a bath of 150 C. After Cooling the preciptate was filtered ofi; the xylene was evaporated from the filtrate in vacuo and the residue was dstilled in vacuo. The yield was 10.5 g. (29%). Boiling point 187 to 189 C./0.1 mm. Bromine content 22.22% (calculated 21.33). By distillation 14.4 g. of 1,6-dbromohexane was regained.

(2) 1 (3,4'5' trmethoxy benzoyloxy) 6 bromohexane.-23.S g. (0.1 mol) of the sodium salt of 3,4,5-trimethoxybenzoic acid and 30 g. (0.12 mol) of 1,6-dibromohexane was added to 300 ml. of anhydrous acetonitrile and the mixture was boiled for 43 hours. The precipitate was filtered ofi and washed with ether. The filtrate was inspissated in vacuo and to the residue was added 150 m1. of ether. The precipitate was filtered off and the ether was vaporated from the filtrate. The residue was distilled in vacuo. The yield was 16.5 g. (44%). Boiling point 186 to 191 C./0.08 mm. Bromine content 24.2% (calculated 21.3%

(b) 1 (3,4',5 trimethoxy benzoyloxy) 6 (N- ethyl-2"-phenylethylamro)hexane.A solution of 10.3

bromohexane and 9 g. (0.06 mol) of N-ethyl-2-phenylethylarnne in 75 ml. of dry benzenewas boiled for 70 hours. The benzene was subsequently evaporated in vacuo and to the residue was added 100 ml. of dry ether. The precipitate formed was filtered ofl and the ether was evaporated from the filtrate. The oily residue had a weight of 11.9 g. and an equivalent weight of 376 (calculated 443). By adding 1 N alcoholc hydrochloric acid solution the substance was converted into the hydrochloride. A few eorts to crystallize this hydrochloride trom methylethylketone, ether and alcohol ether failed. The hydrochloride was obtained in the form of an oil, by evaporating the solvents, and dissolved in 150 ml. of water. This solution was extracted twce with 40 m1. of ether and then alkalized with 10 ml. of concentrated ammonia, after whch extraction was carried out three times with 50 m1. of ether. The ethereal solution was dried on sodium sulphate, filtered off and the ether was evaporated from the filtrate. The residue was found to contain N-ethyl-2-phenylethylarnine and was therefore kept :at 120 C./1 rnm. for three hours. The yield was 2.4 .g. (18%). Eq. weght 440 (calculated 443). U. V. absorption spectrum: =265 mu, e,=11000.

Analysis.-Foundz C 70.02, 69.94%; H 8.43, 8.26%; N 3.07, 3.04%. Calc.: C 70.04%, H 8.35%, N 3.16%.

350 mg. of the base was converted with alcoholic hydrochloric acid into the hydrochloride, which was crystallized from a mixture of methylethylketone and ether.

XV. 1 (3',4',5' trinethoxy benzoyloxy) 4 (N propyl 1" methyl 2" hydroxy 2" phenylethylamrzo)butane hydrochlorde (a) 4 (N propyl 1 methyl 2-oxo-2'-phenylethylamno)butanol-l.-A solution of 6.4 g. (0.03 mol) of 1- oxo-l-phenyl-2-bromopropane and 7.9 g. (0.06 mol) of 4-propylamino-butanol-l in 35 ml. of absolute alcohol was boiled for 15 hours. The alcohol was then evaporated and to the residue was added 50 ml. of ether and 35 m1. of water. The layers were separated and the ether layer was extracted three times with 10 ml. 2 N hydrochloric acid. The three extracts were united and alkalized with 10 ml. of 50% caustc soda and then extracted three times with ether. The ethereal solution was dried on sodium sulphate, filtered o and the ether evaporated from the filtrate. The residue was 7 g. (89%). Eq. weight 259 (calculated 263).

(b) 1 (3',4',5'-trmethoxy benzoyloxy) 4 (N- pr0pyl 1" methyl -2" 0x0 2" phenylethylamirzo) butane hydrochloride.-To a solution of 6.85 g. (0.026 mol) of 4 (N propyl-lmethyl-2-oxo-2-phenylethylamino)butanol-l in 50 m1. of dry benzene was added, within 15 minutes, while stirring, at room temperature a solution of 6.35 g. (0.027 mol) of 3,4,5-trmethoxy-bem zoylchloride in 50 ml. of dry benzene. After the addition the reaction mixture was boiled for three hours and the benzene was evaporated in vacuo. The residue was dissolved in a mixture of 25 m1. of methyl-ethylketone and 25 m1. of ether. The preciptate was filtered o and yielded 3 g. of hygroscopic substance having a chlorine content of 6.79% (calculated 7.19%). Evaporation of the filtrate to 10 m1. yielded a further quantity of hygroscopic substance of 4.5 g. having a chlorine content of 7.19% (calculated 7.19% Yield 7.5 g. (58%). Double crystallisation trom methylethylketone yielded crystals having a melting point of 76 to 79 C.

Analyss.-Fonndt C 62.88%, H 7.39%, N 2.86%, Cl 7.09%, OCH;, 19.15%. Calc.: C 63.22%, H 7.29%, N 2.84%, Cl 7.19%, OCH 18.84%.

(c) 1 (3,4,5' trmethoxy benzoyloxy) 4 (N- propyl 1" methyl 2" hydroxy 2" phenylethylamino)butane hydrochlorde.-To a solution of 2.1 g. (0.0043 mol) of the compound obtained in accordance with Example XVIIb in 50 ml. of 80% alcohol was added palladium catalyst (obtained by hydrogenation of a suspension of 80 mg. of palladium chloride and 350 mg. of decolouring carbon); the mixture was hydrogenated. The hydrogen absorption was performed slowly, so that the hydrogenation was twice interrupted to add fresh catalyst. 116 ml. of hydrogen was absorbed. The reaction mixture was filtered and the solvent was evaporated from the filtrate. The residue was dissolved in a mixture of acetone and ether and kept in the refrigerator. The precipitate was filtered o and dried. The yield was 0.65 g. (31%). Meltng point 133 to 135 C.

After crystallisation from a mixture of alcohol and ether, the melting point was 144 to 145 C. U.V. absorptien spectrum =265 1I1u, e =ll60. The acetoneether filtrate of the first crystallisation was evaporated and the residue dissolved in an alcohol-ether mixture. This yielded a second quantity of crystals: 018 g. (8.5% Melting point 136 to 138 C. U.V. adsorption spectrum =265 m e =11,000. Spasm. act. 30.

Analysis.-Foundz C 62.89, 62.53%; H 7.60, 7.58%; N 2.82, 2.79%. Calc: C 62.96%, H 7.67%, N 2.82%.

(a) I-(4'-benzyloxyphenyl)-2-ntropropene-I.A solution of 100 g. (0.472 mol) of 4-benzylxy4venzaldehyde (J. Chem. 800. 1935, 1540), 47 g. (0.627 mol) of nitroethane and 24 ml. of butylamne in 275 ml. of dry toluene was boiled for 6 hours and the water formed was separated out by distillation. After 6 hours of boiling,

about 9 g. of water had been produced. The toluene was evaporated in vacuo and to the residue was added 150 m1. of petroleum ether (4060 C.). The precipitate was filtered otf, washed with petroleum ether (40- 60) and dried. The yield was 65 g. (51%). Meltng point 132 to 143 C. Crystallsation from tetrahydrofurane yielded yellow, transparent scales, having a melting point of 147 to 148 C.

(b) 1methyl- 2 (4'-benzyloxy)phenylethylamine.-A solution of 45 g. (0.167 mol) of l(4"-benzyloxyphenyl)- 2-nitropropene-l in 500 m1. of dry tetrahydrofurane was added, within 45 minutes, to a solution of 30 g. (0.8 mol) of lithium-aluminium hydride in 300 ml of dry tetrahydrofurane. After the addtion the mixture was hoiled, while stirring, for two hours and the reaction mixture was decomposed subsequently with water, while cooled on ice. The precipitate was filtered off and washed with ether. The solvent was evaporated from the filtrate and the res due was distilled in vacuo. The yield was 26 g. (68%). Boiling point 148 to 152 C./0.07 mm. Melting point 103 to 104 C. Eq. weight 243 (calculated 241).

(c) N acetyl 1 methyl-Z(4'benzyloxy)phenylethylamz'ne.24 g. (0.1 mol) of l-methyl-2-(4'benzyloxy) phenylethylarnine was boiled with 100 ml. of acetic acid anhydride for half an hour. The acetic acid anhydride was evaporated in vacuo and to the residue was added 50 ml. of ether. The precipitate was filtered o1f and washed with 25 ml. of ether. The yield was 23.5 g. (84%). Melting point 123 to 124 C.

((1) N ethyl methyl-2(4'-benzyloxy)phenylethylamne.-The substance was produced in the manner described in Example 1b; the diference =being, however, that tetrahydrofurane instead of ether and N-acetyl-l-methyl- 2-(4-benzyloxy)phenylethylamine was used as starting substance. The yield was 75%. Boiling point 139 to 142 C./0.2 mm. Eq. weight 269 (calculated 269).

(e) N,N ethyl 1 methyl2-(4"-benzyloay)phenylethyl-3-carbaethoxypropionic amz'de.The sulbstance was produced in the manner described in Example XIIa. The yield was 47%.

(f) 4 [N ethyl-1'-methyl2-(4"-benzyl0xy)plzenylet/zylamino]-butanol-I.This substance was produced in the manner described in Example XIb by reducing the compound obtained in the manner described in the preceding paragraph with lithium-aluminium hydride The yield was 50%. Boiling point 186 to 191 C./0.08 rnm. Eq. weight 344 (calculated 341).

(g) 1 (3'4,5' trmethoxy-benzoyloxy)-4-[Nethyl- 1 methyl 2 (4-benzyloxyphenyl)ethylamne] bumne hydrochlorz'de.-This substance was produced in the manner described in Example XIc by reacting the compound obtained by the method described in the preceding paragraph with 3,4,5-trmethoxybenzoylchloride. The yield was 95%. The hydrochlorde did not crystallize. The crude product was therefore hydrogenated.

(h) 1 (34',5 zrmethoxy-benzoyloxy-4-[N-etlzyl- 1 methyl 2 (4"'hydroxyphenyl)ethylamno] butane.'lhe method of producing was similar to that described in Exa-mple XVc by hydrogenating the compound obtained by the method described in the preceding paragraph with palladium catalyst and hydrogen, the dierence being, however, that in thiscase 96% alcohol was employed instead of 80% alcohol. The substance was separated out as a free base. The yield was 25 g. (40%). Eq. weight 430 (calculated 445 Producton of the lzydrchlorde.-O.S g. of the free base was dissolved in the calculated quantity of 0.27 N- alcoholic hydrochloric acid. The alcohol was evaporated and the residue was dissolved in a mixture of acetone and ether. The precipitate was filtered off and dried. The filtrate had a weight of 0.22 g. Melting point 135 to 136 C. U.V. -a=bsorpton spectrum =267.5 to 270 mu, e=600. Spasm. act. 50.

18 Analyss.*Foundz C 62.39, 62.47'%; H 7.61, 7.64%; N 2.91%; Cl 7.37%. Calc.: 62.36%, H 7.48%; N 2.91%, C17.37%

XVII. 1-(3',4,5-trmethoxy-benzoyloxy)4[N-ehyl-I"- methyl 2" (4-methoxyphenyl)et/zylamino]bmane hydrochlorde (a) N,N ethyl 1' methyl-2(4"-methoxyphenyl) ethyl 3 carbaethoxypropionc amide.-The method of producing was similar to that described in Example XIIa by reacting N ethyl 2 (4'-methoxyphenyl)ethylamine with 3-carbaethoxypropionic chloride. The yield was 75%. Boling point 176 to 181 C./0.08 mm.

(b) 4 [N ethyl 1 methyl-2(4-methoxyphenyl) chylamino]bmanol-L-The method of producing was similar to that described in Example Xl b by reducng the compound obtained in XVIIa with lithium-aluminium hydride. The yield was 82%. Boiling point 172 to 179 C./0.2 mm. Eq. weight 265 (calculated 265).

(c) 1 (34',5' trimethoxy benzoyloxy)-4-[N-ethyl- 1" methyl 2" (4'' g methoxyphenyl)ethylamirro] Imzane-hydrochlorde.-The method of producing was similar to that described in Exarnple XIc by coupling the compound obtained in XVIb with 3,45-trimethoxybenzoylchloride. The yield was 69%. The hydrochloride crystalized from methylethylketone with 1 mol of this solvent. This complex had a rnelting point of 77 to 81 C. After the crystallisation from alcohol-ether the hydrochloride was obtained. Melting point 129 to 130 C. U.V. Absorption spectrum =270 m e,=11,200.

Analysis.Found: C 63.11%, H 7.69%, N 2.77, 2.72%; OCH 25.11%. Calc.: 62.96% H 7.67%, N 2.82%, OCH 25.06%. Spasm. act. 125.

XVIII. l-(4',5'trimethoxy-benzoyloxy) 4-[N-ezhyl-I"- methyl 2" hydroxy-2 (4" hydroxyphenyl)ethylamino] butane hydrochlorde (a) 4-[N ethyl 1 methyl-2oxo-Z-(4-benzyloxyphenyl)ethylamino] butanol-I.The method of producing was similar to that described in Example XVa by reacting 1-(4' benzyloxyphenyl)-l-oxo-2-brorno-propane with 4-ethyl-amino-butanol-l. The yield was 38%. Eq. weight 354 (calculated 355).

(b) 1-(3,4,5'-trimetlzoxy-benzoyl0xy) 4-[N-ethyl-I- methyl-Z"-oxo-2"-(4"'-benzyloxyphenyl)ethylamino] butane.-The method of producing was similar to that described in Example XIc by reacting the compound obtained in XVIIIa with 3,4,5-trimethoxybenzoylchloride. The yield was 80%. Melting point 148 to 152 C. Chlorine content 6.43% (calculated 6.06%). Crystallzation from a mixture of alcohol and ether yielded a substance having a melting point of 152 to 153 C. U.V. absorption spectrum =272.5 m;r, e,=31000.

Analysis-Found: C 65.40%, H 6.89%, N 2.32%, OCH 15.79%. Calc.: C 65.58%, H 7.17%, N 2.39%, OCH 15.88%.

(c) 1(3',4,5 trimethoxy-benzoyloxy)-4-[N-ethyll methyl 2- hydroxy-Z-(4-hydroxyphenyl)ethylamino] butane hydrochlorde.The method of producing was similar to that described in Exarnple XVcthe difference being, however, that in this case 96% alcohol nstead of 80% alcohol was used and that, moreover, the compound obtained in XVIIIb was employed as a starting material. The yield was 10%. Melting point 178 to 180 C. U.V. absorption spectrum =267.5 to 270 Illu, e 12,400.

Analyss.-Foundz C 59.42%, H 7.30%, N 2.80%. Calc.: C 60.30%, H 7.24%, N 2.82%. Spasm. act. 75 to 100.

X1X. 1-(3,4'5'-trimethoxy-benzoyloxy) 4-[N-propyl-I- metlzyl 2" hydroxy-Z"-(4"benzyloxyphenyl)ethylamno] buane hydrochloride (a) 4-[N-propyl 1 methyl-2'-0x0 2'-(4"-benzyloxyphenyl)ethylamno] butanol-J.The method of produc- N 2.74%, OCH 18.18%.

'XX. 1-(3',4,5-trmethoxy-benzoyloxy) 4-[1 "-methyl-Z"- Analyszs.-Found: C 65.37%, H 7.02%, N 2.30%,

Cl 6.10%, OCH 15.84%. Calc.: C 66.05%, H 7.34%, N 2.33%, Cl 5.92%, OCH 15.51%.

(c) 1-(3'4,5-trimethoxy-benzoyloxy) 4 [N-propyl- 1" methyl 2" 0x0 2 (4' hydroxyphenyl)ethylamino] bmane hydrochloride.The method of producing was similar to that described in Example XVIIIc by hydrogenating the compound obtained by the method descrbed in the preceding paragraph with palladium and hydrogen. After 1 mol of hydrogen had been absorbed, the reaction was terminated. The yield was 92%. Melting point 192 to 193 C. U.V. absorptior'1 spectrum 7\ =275 m e =20,600; =285 mu,e =2,00.

Analysis.-Found C 61.21%; H 7.10%; N 2.68, 2.61%; Cl 6.97%. Calc.: C 61.23%, H 7.07%, N 2.75%, C1 6.97%.

(d) 1-(3'4'5 trimethoxy-benzoyloxy) 4-[N-propylamino] bmane hydrochloride.-The method of producng was similar to that descrbed in Example XVc by hydrogenating the compound obtained by the method described in the preceding paragraph with palladium and hydrogen, the diflerence being, however, that in ths case use was made of 75% alcohol, instead of 80% alcohol.

The yield was 60%. Melting point 165 to 168 C. U.V. absorpton spectrum: =267.5 to 270 In .=10,200.

AnalyssFoundz C 60.38%; H 7.43%; N 2.79%, 2.72%; OCH 17.82%. Calc.: C 60.99%, H 7.43%,

Spasm. act. 50.

hydroxy 2 (4-hydroxyphenyl) ezhylamino] butane lzydrochloride phenyl)ethylamino] butanol-l.-The method of producing was similar to that described in Example XVa by reacting 1 (4-benzyloxyphenyl)-loxo-2-bromopropane with 4-benzylamino-butanol-l. The yield was 88%. Eq. weght 460 (calculated 417). This crude product was used further.

(b) 1(3,4',5'- zrimethoxy-benzoyloxy) 4-[N-benzyl- 1-methyl-Z"-0xo-2-(4" benzyloxyphenyl)ethylamno] butane hydrochlorde.-The method of producing was similar to that described in Example Xlc by reacting the compound obtaned by the method described in the preceding paragraph with 3,4,5-trimethoxy-benzoylchloride. The yield was 100%. Chlorine content 5.04% (calculated 5.48%). This crude product was used for further purposes.

(c) 1-(3',45' trimethoxy-benzoyloxy)-4-[l-methyl- 2"-0x02-(4"-hydroxyphenyl)ethylamino] butane hydrochlorde.-This substance was produced by the method described in Exarnple XVc by reacting the compound obtained by the method described in the preceding paragraph with palladium catalyst and hydrogen. After the absorption of 2 mols of hydrogen the hydrogenaton was terminated. Use was made of 85% alcohol as a solvent for the compound to be hydrogenated. The yield was 55%. Melting point 135 to 137 C. U.V. absorption spectrum: =275 rnu, e =21,800; 7\ =285 my., e =21,8()0.

Example XXIa with lithium-aluminium hydride.

Analyss.Found: C 58.97%, H 6.55%, C1 7.63%. Calc.: C 59.04%, H 6.42%, Cl 7.59%.

(d) 1-(3',4,5 trmethoxy-benzoyloxy)-4-[l"-methyl- 2"-hydroxy-Z-(4'-lzydroxyphenyl)ethylamno] butane hydrochlorde.The production was the same as that described in Example XVc by hydrogenating with palladium and hydrogen of the compound obtained in XXc. Use was made of 75% alcohol as a solvent for the compound to be hydrogenated. The. yield was 82%. Melting point 190 to 191 C. U.V. absorption spectrum: =267.5 mu. to 270 mu., e =11,000.

Analyss.Found: C 58.31, 58.65%; H 6.70, 6.88%; N 2.96, 2.97%. Calc.: C 58.79%, H 6.82%, N 2.98%. Spasm. act. 0.5.

XXI. 1-(3',4',5'-trimeth0xy-benzoyloxy)-4- (N-propyl- 2"-phenylethylamno) butane hydrochlora'e (a) N .N-propyl-2-phenylethyl-3-carbaethoxy-propionic amde.-A solution of 13 g. (0.08 mol) of 3-carbaethoxy propinoyl-chloride in 70 ml. of dry benzene was added slowly in drops to a solution of 28 g. (0.16 mol) of N- propyl-2-phenylethylamine in m1. of dry benzene. After the addtion the mixture was boiled for two hours and kept at room temperature for one n-ight. The reaction mixture was filtered of and the benzene evaporated from the filtrate. The residue was dsso lved in 100 ml. of dry ether and aftertwo days the precipitate was filtered off again. The filtrate was inspssated and the residue distilled in vacuo. The yield was 22 g. (88%). Boiling point to C./0.04 mm.

(b) 4-(N propyl 2 phenylethylamino)butanol-l The product-ion was carried out by the method described in Example Xlb by reducing the compound obtained in The yield was 75%. Boiling point 140 to 142 C./0.7 rum. Eq. weight 235 (calculated 234).

(c) 1-(3,4,5' trimethoxy benzolyoxy)-4-(N-propyl- 2 phenylezhylamno) butane hydrochloride.--This substance was produced by the method described in Example XIc by reacting the compound obtained in XXIb with 34,5-trimethoXy-benzoylchlorde. The hydrochlorida was crystallized from a mixture of methylethylketone and ether in a ratio of 3:5. The yield was 47%. Melting point 87 to 89 C. Chlorine content 7.61% (calculated 7.62%). Spasm. act. 20. U.V. absorption spectrum: =266 In,u, ,=10100.

Analysis.-Foundz C 64.22, 64.73%; H 7.65, 7.80%; N 3.04, 3.11%. Calc.: C 64.45%, H 7.95%, N 3.01%.

XXH. 1 (3,4',5 trimethoxy-benzoyloxy) 4-[N-propyl- 1-methyl-2-(4'hydroxyphenyl)ethylamno] butane hydrochloride (a) N propionyl 1 methyl-2 (4-benzyloayphenyl) ethylamine.This substance was produced by the method described in Example XVIc by boiling l-methyl-2-(4- benzyloxyphenyl)ethylamine with propionc acid anhydride. The yield was 78%. Melti ng point 95 to 96 C.

(b) N propyl l-methyl-2(4benzyloxyphenyl)ethylamne.This substance was produced by the method described in Example XVId by reducing the compound obtained by the method described in the preceding paragraph with lithium-aluminium hydride. The yield was 77%. Boiling point 172 to C./0.6 mm. Eq. weght 289 (calculated 284).

(c) N,N propyl 1 methyl-2'-(4"-benzyloxyphenyl) ethyl 3 carbaethoxy-proponc amde.The production was carried out by the method described in Example XXIa by reacting the compound obtained by the method described in the preceding paragraph with 3-carbaethoxy propionylchloride. The yield was 87%. Boiling point 208 to 214 C./0.5 mm.

(d) 4 [N-pr0pyl- 1methyl-2-(4'Fbenzyloxyphenyl) etlzylamno] butanol-I.The production was carried out by the method described in Example Xlb by reducing the compound obtained by the method described in the pre- 21 ceding paragraph with lithium-aluminium hydride. The yield was 60%. Boiling point 200 to 205 C./0.1 mm. Eq. weight 358 (calculated 355).

(e) 1 (3,4',5' trimethoxy-benzoyloxy) 4-[N-propyl- 1" methyl-2-(4"-benzyloxyphenyl)ezhylamino]butane hydrochloride.-The production was sirnlar to the method described in Example XIc while the compound obtained by the method descrbed in the preceding paragraph was reacted with 34,5-trimethoxy-benzoylchloride. The yield was 60%. Melting point 138 to 141 C. Chlorne content 6.1% (calculated 6.6%).

(f) 1 (3',4,5' trimethoxy-benzoyloxy) 4-[N-propyl- 1" methyl2-(4"-hydroxyphenyl)ethylamino]butane hydrochloride.-The substance was produced by the method described in Example XVc by hydrogenating the compound obtained by the method descrbed in the preceding paragraph. The yield was 72%. Melting point 172 to 173 C. Chlorine content 7.36% (calculated 7.17%). U.V. absorption spectrum: =268 m,u, e =10,900. Spasm. act. 50.

Analyss.Foundz C 63.11, 63.17%; H 7.76, 7.75%; N 2.55, 2.50%. Calc.: C 62,97%, H 7.67%, N 2.83%.

XXII. 1-(3'4',5' rmethoxy benzoyloxy 4-(N-propyl- 1 "-methyl-2"-phenylethylamino) buzane hydrochlorde (a) N,N propyl 1' methyl-2'-phenylethyl-carbaethoxyprapionc amde.The substance was produced by the method described in Exarnpe XXIa by reacting 3- carbaethoxy-propionyl chloride with N-propyll-methyl- 2-phenylethylarnine. The yield was 68%. 154 to 158 C./0.02 rnm.

(b) 4 (N -propyl-l-methyl-2-phenylethylamno)butanol.This substance was produced by the method described in Exarnple XIb by reducing the compound obtained by the method described in the precedng paragraph with lithium-aluminium hydride. The yield was 80%. Boiling point 144 to 146 C./0.65 min. Eq. weight 246 (calculated 249).

(c) 1 (3,45' trmethoxy-benzoyloxy) 4-(N-propyl- 1" methyl 2 pherzylethylamino)butane hydrochlorde.-The prodnction was carried out similar to the meth- 0d described in Example XIc by reactng the compound obtaned by the method described in the preceding paragraph with 34,5-trimethoxy-benzoylchlorde. The yield was 86%. Melting point 125 to 126 C. Clorne content 7.2% (calculated 7.39%). U.V. absorption spectrum: =266 rnu, e =10,300. Spasrn. act. 20.

Analyss.-Foundz C 64.36, 64.45%; H 7.96, 7.84%; N 3.11, 2.92%. Calc.: C 65.07% H 793%, N 2.92%.

XXIV. 1-(3',4',5-trimetlzoxy-benzoyloxy) 6-[I-methyl- 2"-(4"'-methoxyphenyl)ethylamino]hexane hydrochlorde A solution of 7.7 g. (0.04 mol) of Nethyl-l-methyl-2- (4'-methoxyphenyl)ethylamine and 6.6 g. (0.02 mol) of 1 (3,4,5-trimethoxybenzoyloxy)-6-bromohexane in 50 1111. of dry acetontrile was boiled for 90 hours. The acetonitrile was evaporated in vacno and to the residue was added 50 m1. of dry ether. The precipitate was fi1- tered off and the ether evaporated from the filtrate. The residue was dissolved in 45 1111. of 0.5 N hydrochloric acid and this soluton was washed twce with 25 m1. of ether. The water layer was alkalized with m1. of concentrated ammonia and extracted three times with 30 m1. of ether. The ethereal extracts were dried on Na SO filtered and the ether evaporated. The residue was kept, for three hours, in vacuo (0.1 mm.) at 90 C. and then dissoved in 24 m1. of 0.76 N alcoholic hydrochloric acid. The alcohol was evaporated and the residue crystallized from a mixture of m1. of methyl-ethyl ketone and 10 m1. of ether. The yield was 6.0 g. (60%). Meltng point 137 to 140 C. Chlorine content 7.03% (calculated 6.78%). U.V. absorption spectrum: =267.5 m e,=12,600.

Boling point XXV. 1 (3',4,5 trimethoxy-benz0yloxy) 3 [N-ethyl- 1"-methyl-2(4-methoxyphenyl) ethylamno] propane (a) 1 (3,4',5 trmethoxy-benzoyloxy)-3bromopropane.The prodncton was carried out similar to the method described in XIV a by esterifyng the sodium salt of 3,4,5-trimethoxy-benzoic acid with 1.3 dibromopropane. The yield was 52%. Boiling point 165 to 169 C./0.3 mm. Bromine content 23.7% (calculated 24%).

(b) Z-(3',4',5' trimezhoxy benzoyloxy) 3-[N-ethyl- 1" methyl-Z (4"' methoxyphenyl) ethylamino] propane.-The production was smlar to the method described in XXIV by couplng the compound described in the precedng paragraph with N-ethyIJ-rnethyl-2-(4- methoxyphenyl)ethylarnine. The yield was 54%. Eq. weight 432 (calculated 445). U.V. absorption spectrum: =27.5 m e =11,600. Spasm. act. 25.

XXVI. 1-(3,4,5-trethoxy-benzoyloxy) 4-(N-propyl-I"- methyl-2"-phenylethylamno)butane hydrochlorde The production was Carried out by a method similar to the method described under Xc by esterifying 4-(N- propyl l'-methyl-2-phenyl ethylamino)butanol-l (sec XXIIb) with 34,5-trirnethoxybenzoylchloride. The yield wa Meltng point 123 to 124 C. Chlorine content 6.77% (calculated 6.81%). U.V. absorption spectrum: =266 m e =9,600.

Analysis.-Foundz C 67.15%, H 8.36%, N 2.74%. Calc.: C 66.73%, H 8.44%, N 2.68%.

XXVII. 1-(3,4',5'trimethoxy-benzoyloxy) 4-[N-ethyl- 1-methyl-2"-(4-methoxyphenyl)ethylamno] bmane hydrochlorize The producton was smilar to the method described in XIc by esterifying 4-[N-ethyl-1'-rnethyl-2-(4methoxyphenyl)ethylamino]butanol-1 (see XVIb) with 3,45 trimethoxy benzoylchloride. The yield was 75%. Melting point 92 to 106 C. Chlorne content 6.93% (calculated 6.60% U.V. absorption spectrum: =27 nm, e =l0.200. Crystallization from methyiethyl ketone yielded a substance having a meltng point of 119 to 120 C. Spasm. act. '30.

XXVIII. 1 (3',4,5 trmethoxy-benzoyloxy) 4 [N- ethyl 1 methyl 2 (3,4 dimethovcyphenyl) ethylamno]butane hydrochloride (a) I-(3',4'-dimethoxyphenyl) 2(N-ethylamno)propane.-The method use'd was a catalytic hydrogenation of a mixture of 1-(3',4'-dirnethoxyphenyl)propanone-2 (I. Am. Chern. Soc. 66, 26 (1944)) and ethylamine with platinum as a catalyst. The yield was 81%. Boiling point 162 to 165 C./ 13 mm. Eq. weght 229 (calculated 223).

(b) N,N ethyl 1 methyl 2 (3",4"-dimethoxyphenyl)ethyl-3-carbaetlzoxy-propionic amde.-This substance was produced by a method smilar to the method described in XXIa by reacting the compound described in the preceding paragraph with 3-carbaethoxy-propionyl chloride. The yield was 100%. The nondstilled product was employed for the reaction to be described hereinafter.

(c) 4 [N-ethyl-Z'metlzyl2-3,4"-dimethvxyphenyl)] ezhylamno butanol-J.The method used was similar to the method described in Xb by reducing the compound descrbed in the preceding paragraph with a solution of lithium-aluminium hydride in ether. The yield was 70%. Boiling point 165 to 168 C./0.08 mm. Eq. weight 297 (calculated 295).

(d) 1-(3,4,5'-trimethoxy-benzoyloxy) 4-[N-ezhyl-I- mezhyl 2" (3',4"-dmeflzoxyphenyl)ethylamna]butarze hydrochloride.The productiori was carried out by a method similar to the method described in XIc by esterifying the compound described in the preceding paragraph with 34,5-trimethoxy-benzoylchloride. The yield was 70%. Melting point 129 to 132 C. Chlorne content 6.78% (calculated 6.76%). U.V. absorption spectrum: =269 m/u, e 12,600. Crystallsation from meth- XXXV.

25 Analysis.-Fund: 0 57.72% I-I 7.57%, N 2.81%, ocnr 16.73%. C811C2 c 61.00%, H 7.43%, N 2.74%, ocra 18.18%.

(2.) 1-(3',4,5-rmethoxybenzoyloxy) -b10m0penuwer-The production was carried out similar to the method described in XIVa by esterfying the sodiurn salt of 3,45-rrimethoxy-benzoic acid with 1,5-dibromopentane. The yield was 56%. Boiling point 182 to 196 C./0.05 mm. Melting point 7981 C. Bromine content 22.2% (calculated 22.1%

(b) 1-(3,4,5'-trimethoxy-benmyloxy)5-[N-ethyl-I"- methyl 2"-(4"methoxyphenyl)ethylamin0]pentane. The production was sirnilar to the method described in XXIV by coupling the compound described in the precedng paragraph with N-ethyl-l-methyl 2(4-methoxyphenyl)ethylamine. The yield was 58%. Eq. weight 473 (calculated 473). U.V. absorption spectrum: =267 m;r, e =11,900. Spasm. act. 250.

Analyszs.-Foundz C 67.76% H 8.40%, N 2.71%. Calc: C 67.56%, H 8.21%, N 2.96%.

Ths product was preparcd according to the same method as set out in Example XXI. First 3-carbaethoxy propionylchloride was reacted with N-ethyl 2-(2-me- Ths product was prepared according to the same process as indicated in the foregoing examples. Firstly l-[N- ethyl-2-(3"-methoxyphenyl)-l-methyl ethylamino] 3- carbaethoky propionic amide (boiling point 184190 C./ 0.3 mm. Hg) was prepared from 3-carbaethoxy propionyl chloride and N-ethyl 2-(3"methoxyphenyl)-l'-methyl ethylarnine. Then the carbaethoxy compound was reduced to obtain 4-[N-ethyl-2'-(3-methoxyphenyl)l'- rnethyl ethylamino] butanol-l (boiling point 148 152 0/ 0.4 mm. Hg) which compound was esterified with 3,4,5-trirnethoxy benzoic acid to obtain the compound as mentioned in the beginning of this example after acidifying with HC1. Melting point of the substance 119.5 122 C. U.V. absorption spectrum: =269 m, =11,900

Analyszs.-C 63.07%; (calc. 62.97% H 7.75% (calc. 7.67%), N 2.86% (calc. 2.83%), C1 7.16% (calc. 7.16% Spasm. act.: Doryl-papaverine 65-125; BaCl =papaverine 5-10.

XXXIX. 1-(3'4,5-trimethoxy-benzoyloxy)-5-[N-ethyl 2"-(2 mehoxyphenyl) 1 melhyl ethylamno] pentane.

The procedure was the same as indicated in Example XXXVI. =28 m;r, e =11.500.

Analyss: C 68.35% (calc. 68.56%), H 8.25% (calc. 8.31%), N 3.11% (calc. 2.96%). Hydrochloride salt rnelting point 1111 14 C.; Cl content 7.20% (calc. 6.95%). U.V. absorptin spectrum: =267 m e =11.900. Spasm. act.: Doryl-papaverinc=65 BaCl;,-papaverine=S-IO.

The antispasmodic activity of the neurotropic type of the compounds of the invention was determined in vitro against carbarninoylchlorene (Doryl) by the method of Magnus, described in Pfliigers Archiv (102, page 123 and ff. (1904)). By this method there is measured the contraction of an intestine under the action of a solution of known concentration of carbarninoylcholine, i.e. a spasmogen having a neurotropic eect. It is then determined which concentration of papaverine is required to obviate the said contraction for 50% and then the concentration of a compound to be tested which is also capable to obviate the said contraction for 50%. The quotient of the concentration of papaverine and the tested compound producing the obviation of 50%, is a measure for the antispasmodic activity (in .his case of neurotropic nature). Ths activity is also indicated in the tables.

If previously a fairly high antispasrnodic eiect of neurotropic nature in vitro had been ascertained with compounds of the invention, an antispasmodic effect of musculotropic nature is measured by use of barium chloride as a spasrnogen.

For the increasing of spasmolytic activity it has been found that alkoxy groups present on the left hand benzene nucleus of the compounds of Formula A should preferably be methoxy or ethoxy, particularly at the para or para and meta positions,R should be preferably alkyl, particularly methyl.

A particular group of compounds of Formula A having a high spasmolytic activity are those compounds in which R is hydrogen, R is hydrogen or alkoxy of 1 to 4 carbon atorns, R is hydrogen or hydroxy, R is hydrogen or alkyl of 1 to 4 carbon atoms, R is alkyl of 1 to 6 carbon atoms, Y is alkylene of 3 to 7 carbon atoms, R is hydrogen or alkoxy and R is alkoxy.

A particularly preferred group of these latter compounds are those in which R is hydrogen, R is hydrogen, para-methoxy or para-ethoxy, R is meta-methoxy, or meta-ethoxy, R; is hydrogen, R is hydrogen or methyl, R is alkyl of 2 to 3 carbon atoms, Y is alkylene of 4 to 6 carbon atoms, R is hydrogen, para-methoxy or paraethoxy and R is meta-methoxy or meta-ethoxy.

In the compounds of our invention falling within the scope of Formula B it has been found that the following groupings of substituents tend to increase the spasmolytic activity:

I. The group in which:

R and R are hydrogen, R is hydrogen or para-hydroxy, R, is hydrogen or hydroxy, R is methyl, R is alkyl of 1 to 5 carbon atorns, Y is alkylene of 1 to 8 carbon atoms or an alkyl-cyclohexyl group and R R and R are each methoxy bound to carbon atoms 3, 4 and 5 of the righthand benzene nucleus;

II. The group in which:

R is hydrogen or meta-methoxy, R is para-methoxy, R; is hydrogen, R; is hydrogen, R is methyl, R is alkyl of 1 to 4 carbon atoms, Y is alkylene of 2 to 8 carbon atoms and R7, R and R are methoxy or ethoxy at positions 3, 4 and 5 respectively of the right-hand benzene nucleus.

Finally a group of compounds falling within the scope of Formula B having spasmo.lytic activity of both neurotropic and musculotropic nature are those compounds in which R and R are hydrogen, R is para-ethoxy or paramethoxy, R; is hydrogen or hydroxy, R is methyl, R is alkyl of 2 to 3 carbon atorns, Y is alkylene of 2 to 5 carbon atoms and R R and R are methoxy groups joined to the right-hand benzene nucleus at the 3, 4 and 5 positions.

29 ach selected from the group consstng of OH and alkoxy of 1-4 carbon atoms and ther non-toxic acid additon salts.

2. A compound of the formula CH CH3 l OOH; C Ha 3. A compound of the formula 11. A compound of the formula oc H;

0 no@c Ho HNC mc momomo- OCHs (!H3 (JJH2 l z References Cited by the Examiner 10 FOREIGN PATENTS UNITED STATES PATENTS 232,206 2/ 1926 Great Britan.

2,404691 7/ 1946 Christansen et al. 260-473 2,650230 8/1953 Cusic LORRAINE A. WEINBERGER, Prlmary Exammer. 2,995492 8/1961 Biel 260+294.3 15

3,004976 10/1961 Marxer 260-294.3

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3254112 May 31, 1966 Teunis Kralt et al It is hereby certfed that error appears in the above numbered patent requiring correction and that the sad Letters Patent should read as corrected below.

Column 4, line 22, strike out "formula Xll contains, between the nitrogen atom and" and nsert 1nstead formulae Hlg is a chlorine atom, a bromne atom or an column 8, lnes 8 and 9, for "thereal", each occurrence, read ethereal line 29, for "2, read a column 9,

line 43, for "7471%" read 6471% line 71, for "methyl 2 3 4 read methyl -2 [3 4 column 10, line 70, for "alcohol" read alcoholic column ll, line 28, for "l-(4-methoxy" read l- [4methoxy column 12, line 11, for "and" read had line 35, for "IIb" read IIIb column 15, line 27', for "21.33" read 2l.33% column l, line 62, for "adsorpton" read absorption column l7, line 6, for "152" read 142 column l8, line 2, for "62.56" read C 62,36% line 32, for "62.96%" read C 62,96% column 2l, line 34, for "tanol," read tanol-l line 50, for "795%" read 793% column 22, l1ne 36, for "trimethoxy" read criethoxy line 60, for "2-3," read 2 [3" column 25 line 23 for "8 21%" read 8.31% column 26, line 9, for "carbaminoylchlorene" read carbaminoylcholine columns 27 and 28, 1n the table for Compounds of Formula B", column 4, l1ne 2 thereof, for H read H same table, column l line 19 thereof, for "oOCH read mOCIL same table, column line 19 thereof, for "nC H reed C ,H columns 29 and 30, for the porton of the formule in claim 5 reading read

Claims (1)

1. AN ARALKYLAMINO ESTER OF A NUCLEAR SUBSTITUTED BENZOIC ACID SELECTED FROM THE GROUP CONSISTING OF THE FREE BASE OF THE FORMULA:

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